Using perturbation theory, a working principle has been established for predicting the reactions of aromatic electrophilic carcinogens with nucleic acid bases. The success of this approach in a relatively crude form now requires that it be further developed to accurately predict the relative yields and identities of potential reaction products. This development will consist of using IEHT, and possibly MINDO/3, calculations to predict rates of reaction of carcinogens, to determine extent of solvent competition for transient intermediates, as a source of parameters for studies of perturbation interactions with nucleic acid bases, to determine energy differences due to steric hindrance, and as the source for calculating electrostatic potential energy maps. It is expected that the combination of electrostatic potential with perturbation interactions will predict product identity with high reliability, while the other factors mentioned will determine overall yields. Further testing of these predictions will be carried out using precursors of N-aryl-N-acetylnitrenium ions not yet investigated. The binding and susceptibility to repair of several N-arylacetamides in human fibroblasts will be determined in collaboration with V.M. Maher and J.J. McCormick. The binding of labeled N-acetoxy-N-arylacetamides to components of rat liver chromatin will be determined in vitro, together with the binding of selected aromatic amides to chromatin components in male and female rat liver and female rat mammary gland. By combining theoretical chemistry, in vitro organic chemistry, and in vivo binding studies in one laboratory, the investigators will be able to evaluate results from each research area in the light of other ongoing efforts, and initiate new research directions on the basis of apparent contradictions appearing in the interactions of these several fields.